A central goal of our research is to understand the mechanisms that enable arthropod-borne viruses (arboviruses) to emerge from sylvatic, zoonotic cycles into circulation among humans, thereby causing endemic or epidemic disease. In this project, we will investigate the mechanisms by which 2 arboviruses with important public health impacts, dengue (DENV) and chikungunya viruses (CHIKV), emerge from sylvatic cycles in non-human primates in Senegal to circulate among humans. The results will be critical for assessing the feasibility of strategies to control or eradicate these pathogens when vaccines become available. DENV and CHIKV are ideal viruses to study in tandem in this region because they share vectors and reservoir hosts, their history of emergence has been investigated through extensive genetic studies, and they have been under continuous surveillance in Senegal by the Institut Pasteur since 1972. Endemic/epidemic DENV infects 100 million people per year in over 100 countries, causing classical dengue fever as well as dengue hemorrhagic fever and dengue shock syndrome, while CHIKV has caused recent epidemics involving over 2 million persons with severe arthritic disease. Our previous studies indicate that DENV-1, -2 and -4 evolved independently from ancestral, sylvatic DENV strains that circulate in West Africa and Malaysia, where they are transmitted among nonhuman primate reservoir hosts by arboreal Aedes spp. mosquitoes. Moreover, we have generated phylogenetic evidence that CHIKV originated in Africa, where it persists in a sylvatic cycle, and subsequently spread to Asia where it circulates among humans in urban settings. However the mechanisms involved in generating the endemic/epidemic cycles of each of these viruses are unknown. In the proposed research, we will investigate prospectively the degree and nature of contact between humans and the sylvatic transmission cycles of DENV and CHIKV, and the potential for this contact to lead to emergence. We hypothesize that 3 factors determine the probability of emergence of a sylvatic arbovirus: (i) the temporal and spatial dynamics of the virus in its sylvatic cycle, (ii) the degree of contact between humans and the sylvatic cycle, and (iii) the magnitude of genetic change required for the sylvatic strains to circulate among humans. We will integrate modeling and field studies to generate tools that can be used to predict the risk of human infection and emergence. The results of this multidisciplinary project will improve our understanding of emergence mechanisms of DENV, CHIKV and other zoonotic, sylvatic arboviral pathogens including Zika virus, another arbovirus enzootic in eastern Senegal that recently emerged in Micronesia to cause a DEN-like epidemic. Other major benefits include (i) characterization of a wide variety of arboviral febrile disease etiologies in West Africa, where there is little known about their disease burden;(ii) improved clinical diagnostics in eastern Senegal, (iii) identification of risk factors for arboviral infections, and (iv) training of young American and Senegalese scientists in both field and laboratory approaches to studying emerging arboviral diseases. PUBLIC HEALTH RELEVANCE: We will investigate the mechanisms by which 2 arboviruses with important public health impacts, dengue (DENV) and chikungunya viruses (CHIKV), emerge from a sylvatic cycle in non-human primates in Senegal to circulate among humans. We will investigate prospectively the degree and nature of contact between humans and their sylvatic transmission cycles, and the potential for this contact to lead to emergence. The results will improve our understanding of emergence mechanisms of DENV, CHIKV and other zoonotic, sylvatic arboviral pathogens including Zika virus, another arbovirus enzootic in eastern Senegal that recently emerged in Micronesia to cause a DEN-like epidemic.